A new method to detect related function among proteins independent of sequence and fold homology
A new method to detect related function among proteins independent of sequence and fold homology
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DOI：
10.1016/s0022-2836(02)00811-2
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发表时间：
2002-10-18
影响因子：
5.6
通讯作者：
Klebe, G
中科院分区：
文献类型：
--
作者：
Schmitt, S;Kuhn, D;Klebe, G
开发了一种新的方法来检测独立于给定序列或折叠同源性的蛋白质之间的功能关系。它基于这样一种观点，即蛋白质的功能与对底物或内源性配体在一个特征良好的结合口袋中的结合的识别和随后的反应密切相关。因此，需要保守的识别特征暴露在共同的物理化学相互作用特性方面，通过特定结合腔两侧残基的官能团。遵循小分子配体比较中常用的技术，为从整个PDB中提取并存储在数据库Cavbase中的大量空腔样本集分配了可能相互作用特性的通用伪中心编码。利用特定的查询空腔，基于团检测算法检测出一系列相似度递减的相关空腔。检测到的相似度根据不同团解共享的基于属性的表面补丁进行排序。该方法可以检索容纳相同（例如辅助因子）或密切相关配体的蛋白质空腔，也可以提取在相关催化机制方面表现出相似功能的蛋白质。最后，这种新方法在从头设计中有很强的潜力提出替代分子骨架。检索与药物设计研究的蛋白质的口袋相似的特定子口袋中的分子构建块可以激发新配体的发现。(C) 2002 Elsevier Science Ltd.版权所有。
A new method has been developed to detect functional relationships among proteins independent of a given sequence or fold homology. It is based on the idea that protein function is intimately related to the recognition and subsequent response to the binding of a substrate or an endogenous ligand in a well-characterized binding pocket. Thus, requires conserved recognition features exposed in terms of common physicochemical interaction properties via the functional groups of the residues flanking a particular binding cavity. Following a technique commonly used in the comparison of small molecule ligands, generic pseudocenters coding for possible interaction properties were assigned for a large sample set of cavities extracted from the entire PDB and stored in the database Cavbase. Using a particular query cavity a series of related cavities of decreasing similarity is detected based on a clique detection algorithm. The detected similarity is ranked according to property-based surface patches shared in common by the different clique solutions. The approach either retrieves protein cavities accommodating the same (e.g. co-factors) or closely related ligands or it extracts proteins exhibiting similar function in terms of a related catalytic mechanism. Finally the new method has strong potential to suggest alternative molecular skeletons in de novo design. The retrieval of molecular building blocks accommodated in a particular sub-pocket that shares similarity with the pocket in a protein studied by drug design can inspire the discovery of novel ligands. (C) 2002 Elsevier Science Ltd. All rights reserved.